While bisphenol A is a known endocrine-disrupting compound (EDC), its substitute bisphenol S has been shown to be worrisome as well. Three new studies add more evidence that exposure to these EDCs early in life will likely lead to serious health issues later in life.

Once again, bisphenol A (BPA) is making headlines, and, as always, not in a good way. Hundreds of epidemiological studies have been published that link BPA, a known endocrine-disrupting compound (EDC) even at very low doses, to health problems affecting all human body systems. Two new studies raise yet more cause for alarm, and a third demonstrates that a commonly used BPA substitute is probably not much better for human health. Collectively, these studies contribute to the burgeoning body of evidence that exposure to EDCs during critical developmental periods predisposes the individual to serious disease.

“With BPA found in everything from tomato soup can linings, to beer cans, to gas station receipts, it’s vitally important to understand how this and other EDCs affect brain function.” – Alfonso Abizaid, PhD, Carleton University, Ottawa, Canada

Once again, bisphenol A (BPA) is making headlines, and, as always, not in a good way. Hundreds of epidemiological studies have been published that link BPA, a known endocrine-disrupting compound (EDC) even at very low doses, to health problems affecting all human body systems. Two new studies raise yet more cause for alarm, and a third demonstrates that a commonly used BPA substitute is probably not much better for human health. Collectively, these studies contribute to the burgeoning body of evidence that exposure to EDCs during critical developmental periods predisposes the individual to serious disease.

BPA and Obesity

In “Perinatal Exposure to Low-Dose Bisphenol-A Disrupts the Structural and Functional Development of the Hypothalamic Feeding Circuitry,” published in Endocrinology, Alfonso Abizaid, PhD, of Carleton University in Ottawa, Canada, and team followed up on existing studies that demonstrated how exposure to BPA in the early postnatal period affects body weight, glucose homeostasis, and liver function in mice to confirm that the metabolic impairments were the result of the exposure rather than a function of their postnatal environment or a certain metabolic phenotype.

“With BPA found in everything from tomato soup can linings, to beer cans, to gas station receipts,” Abizaid says, “it’s vitally important to understand how this and other EDCs affect brain function.” The researchers fed pregnant CD-1 mice a diet of food containing BPA, notably, “at doses lower than levels deemed safe by the U.S. Food and Drug Administration and Health Canada,” Abizaid says. Another cohort of dams was given diethylstilbestrol (DES), and a third chemical-free group represented the control. Offspring were intraperitoneally injected with recombinant mouse leptin, the so-called “satiety hormone,” at various time points and then euthanized at different ages for analysis of brain tissue and blood to determine their response to the leptin. As part of the melanocortin system important in energy-balance signaling, a postnatal surge in circulating leptin is thought to encourage the development of projections from pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, a group of cells that are critical for the regulation of feeding and body weight.

Their findings revealed that the BPA-exposed mice had fewer POMC projections and a delayed leptin surge and therefore decreased sensitivity to leptin. Likewise, the leptin surge was blunted in DES-exposed mice. In females only, POMC projections later developed normally with daily injections of supplemental leptin. This implicates BPA as an obesogen, reprogramming the melanocortin system and irrevocably disrupting metabolic homeostasis.

Because, as Abizaid puts it, “if it happens in animals, it is likely to happen in humans,” his team is in the process of conducting research in humans and to determine if these changes are reversible. “Pregnant humans have enzymes that break down BPA within 30 minutes,” Abizaid says. “But fetuses and newborns do not have these enzymes. We need to understand what BPA is doing to us and make a serious attempt to reduce BPA levels in consumer products as potentially another means to reverse the obesity epidemic.”

BPA’s Effects on the Developing Liver

In “Early Life Environmental Exposure Creates ‘Super-Promoters’ By Developmentally Reprogramming the Epigenome of Genes Associated with NAFLD,” presented at ENDO 2017, a team of researchers led by Lindsey Treviño, PhD, of Baylor College of Medicine in Houston, Texas, sought to identify the molecular causes of the developmental reprogramming they had observed in past animal studies. “Early-life exposure to BPA in rodents leads to the development of non-alcoholic liver disease (NAFLD) in adulthood, a phenotype exacerbated by challenge with high-fat diet,” Treviño says. “However, there is a gap in our knowledge regarding alterations in the epigenome in these models, particularly those alterations that precede overt liver disease and may play a role in modifying disease susceptibility.”

Researchers exposed newborn rat pups to environmentally relevant doses of three oral doses of BPA over a five-day period and compared their liver tissue either postexposure or during adulthood to control samples. Analysis of liver samples showed increased liver weight as well as increased levels of serum triglycerides, low- and very-low-density lipoprotein, and free cholesterol in BPA-exposed rats, suggesting that BPA had developmentally reprogramed their livers and predisposing them to a NAFLD phenotype.

“Exposure of developing tissues or organs to an adverse stimulus during critical periods of development can permanently reprogram normal physiological responses contributing to the development of disease later in life, Treviño explains. “Importantly, different tissues may have very different windows of susceptibility, and epigenomic alterations can persist across the life course (or even across generations).” In rats, five days after birth is one such window for liver. The team plans to continue examining molecular mechanisms underlying epigenomic changes. “We are also interested in translating these data into humans by examining whether the observed epigenomic changes, and/or associated changes in gene expression, metabolites, and lipids, are also observed in people at risk for NAFLD,” Treviño says. “Even though the direct relevance of our data to human health is still being tested, it is clear that increasing awareness of EDC exposures and their potential health effects is warranted. Clinicians who treat patients from particularly vulnerable populations, such as pregnant women and children, can play a greater role in determining potential EDC exposures of patients and in educating patients about minimizing these exposures where possible.”

“BPA-Free” Is No Guarantee

In “Regulation of Estrogen Receptor (ER) and BRCA1 By Bisphenol-S (BPS) in Breast Cancer Cells,” also presented at ENDO 2017, Sumi Dinda, PhD, of Oakland University School of Health Sciences in Rochester, Mich., and his team investigated whether the bisphenol analogue BPS is a suitable alternative to BPA in many everyday products. BPS is commonly used in products labeled “BPA free” as well as in plastic substitutes and even paper currency.

“Clinicians who treat patients from particularly vulnerable populations, such as pregnant women and children, can play a greater role in determining potential EDC exposures of patients and in educating patients about minimizing these exposures where possible.” – Lindsey Treviño, PhD, Baylor College of Medicine, Houston, Texas

EDCs interfere with the normal hormonal activity in the body, and bisphenols, specifically, disrupt the proper functioning of estrogen receptors. “Studies suggest BPS induces ERα pathways via its estrogen-mimicking properties in the body, causing increased cell proliferation and resulting in increased breast cancer risk,” Dinda says. “Despite the hope of a safer substitute, studies have shown that BPS exhibits similar estrogenic activity compared to its analogue BPA, due to their structural commonalities.” As most breast cancers are ER positive, and the majority of women who inherit a harmful mutation in the BRCA1 gene will develop breast cancer, the team sought to elucidate the relationship between ERα, BRCA1 expression, and BPS for better understanding of breast cancer treatment and prevention.

Exposing two ER-positive breast cancer cell lines to BPS or to an inactive control, they found that BPS behaved like estrogen by increasing protein expression in ER and BRCA1 after 24 hours. After six days, the BPS-exposed breast cancer cells had proliferated exponentially. When next treated with anti-estrogen agents, the breast cancer cells ceased multiplying.For oncologists dealing with breast cancer patients, Dinda advises, “be knowledgeable about the potential health risk of BPS since it may cause the cancer to be aggressive due to its interaction with estrogen receptor and BRCA1 genes.” He and his team are currently conducting additional studies with BPS on breast cancer cells.

– Horvath is a freelance writer based in Baltimore, Md. She wrote about pediatric obesity studies in the June issue.